Spatial and Phenotypic Characterization of Vascular Remodeling in a Mouse Model of Asthma

Su, Xinming; Taniuchi, Namiko; Jin, Enjing; Fujiwara, Masakazu; Zhang, Lei; Ghazizadeh, Mohammad; Tashimo, Hiroyuki; Yamashita, Naomi; Ohta, Ken; Kawanami, Oichi

doi:10.1159/000113794

Cited by 15 publications

(8 citation statements)

References 61 publications

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“…4A bottom panels). Since deficiency of either Flk-1 or Foxf1 in mice was associated with severe lung injury and inflammation (35–38), the reduced expression of these genes may contribute to the increased inflammation seen in enFoxm1 −/− lungs following urethane treatment. Interestingly, the decreased Flk-1 and Foxf1 mRNAs were also observed in enFoxm1 −/− lungs prior to urethane treatment (Fig.…”

Section: Resultsmentioning

confidence: 99%

Endothelial Cell–Specific Deletion of Transcription Factor FoxM1 Increases Urethane-Induced Lung Carcinogenesis

et al. 2011

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Vascular endothelial cells provide essential support to the tumor microenvironment, but little is known about the transcriptional control of endothelial functions during tumorigenesis. Here we define a critical role for the Forkhead transcription factor FoxM1 in modulating the development of tumor-associated endothelial cells. Pulmonary tumorigenesis induced by urethane administration was compared in mice genetically deleted for FoxM1 in endothelial cells (enFoxm1 À/À mice). Notably, lung tumor number and size were increased in enFoxm1 À/À mice. Increased tumorigenesis was associated with increased proliferation of tumor cells and increased expression of c-Myc and cyclin D1. Furthermore, perivascular infiltration by inflammatory cells was elevated and inflammatory cells in BAL fluid were increased. Expression of Flk-1 (vascular endothelial growth factor receptor 2) and FoxF1, known regulators of pulmonary inflammation, was decreased in enFoxm1 À/À mice.siRNA-mediated knockdown of FoxM1 in endothelial cells reduced Flk-1 and FoxF1 expression, which was driven by direct transcriptional induction by FoxM1 as target genes. Endothelial specific deletion of FoxM1 in vivo or in vitro also decreased expression of Sfrp1 (secreted frizzled-related protein 1), a known inhibitor of canonical Wnt signaling, in a manner that was associated with increased Wnt signaling. Taken together, our results suggest that endothelial-specific expression of FoxM1 limits lung inflammation and canonical Wnt signaling in lung epithelial cells, thereby restricting lung tumorigenesis. Cancer Res; 71(1); 40-50. Ó2011 AACR.

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Section: Resultsmentioning

confidence: 99%

Endothelial Cell–Specific Deletion of Transcription Factor FoxM1 Increases Urethane-Induced Lung Carcinogenesis

et al. 2011

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“…VEGF, an important angiogenic growth factor, also contributes to non-specific airway hyper-responsiveness, has chemotactic effects on eosinophils, and enhances airway smooth muscle cell proliferation (21, 22). VEGF is expressed in human and mouse lungs where it has an important role in lung development.…”

Section: Discussionmentioning

confidence: 99%

IgE mediates broncho-vascular remodeling after neonatal sensitization in mice

et al. 2016

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The temporal origins of childhood asthma are incompletely understood. We hypothesize that allergen sensitization which begins in early infancy causes IgE-mediated airway and vascular remodeling, and airway hyper-responsiveness. Mice were sensitized with ovalbumin (OVA) without or with anti-IgE antibody from postnatal day (P) 10 through P42. We studied airway resistance in response to Methacholine (MCh) challenge, bronchoalveolar lavage fluid (BAL) inflammatory cell content, immunohistochemistry for inflammation, alpha-smooth muscle actin (alpha-SMA) and platelet/endothelial cell adhesion molecule (PECAM) proteins, and Western blotting for vascular endothelial growth factor (VEGF) protein. Compared to controls, mice treated with OVA had increased airway resistance (baseline: 192% of control; MCH 12 mg/ mL 170% of control; P less than 0.0.5). OVA treatment also increased lung alpha-SMA, VEGF and PECAM compared to controls. Inflammatory cells in the BAL and perivascular and peribronchiolar inflammatory cell infiltrates increased over controls with OVA exposure. These changes were counteracted by anti-IgE treatment. We conclude that mice sensitized in early infancy develop an IgE-mediated hyper-reactive airway disease with airway and vascular remodeling. Preventive approaches in early infancy of at-risk individuals may reduce childhood asthma.

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“…The formation of new blood vessels is a characteristic feature of chronic inflammatory diseases, including asthma. Indeed, in asthmatic patients the degree of bronchial vascularity is thought to contribute to airflow limitation [11, 28–31]. Furthermore, increased expression of proangiogenic mediators and their receptors has been correlated with disease severity and accelerated decline in lung function [32, 33].…”

Section: Discussionmentioning

confidence: 99%

CXCR2 Mediates the Recruitment of Endothelial Progenitor Cells During Allergic Airways Remodeling

et al. 2009

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Airway remodeling is a central feature of asthma and includes the formation of new peribronchial blood vessels, which is termed angiogenesis. In a number of disease models, bone marrow-derived endothelial progenitor cells (EPCs) have been shown to contribute to the angiogenic response. In this study we set out to determine whether EPCs were recruited into the lungs in a model of allergic airways disease and to identify the factors regulating EPC trafficking in this model. We observed a significant increase in the number of peribronchial blood vessels at day 24, during the acute inflammatory phase of the model. This angiogenic response was associated with an increase in the quantity of EPCs recoverable from the lung. These EPCs formed colonies after 21 days in culture and were shown to express CD31, von Willebrand factor, and vascular endothelial growth factor (VEGF) receptor 2, but were negative for CD45 and CD14. The influx in EPCs was associated with a significant increase in the proangiogenic factors VEGF-A and the CXCR2 ligands, CXCL1 and CXCL2. However, we show directly that, while the CXCL1 and CXCL2 chemokines can recruit EPCs into the lungs of allergen-sensitized mice, VEGF-A was ineffective in this respect. Further, the blockade of CXCR2 significantly reduced EPC numbers in the lungs after allergen exposure and led to a decrease in the numbers of peribronchial blood vessels after allergen challenge with no effect on inflammation. The data presented here provide in vivo evidence that CXCR2 is critical for both EPC recruitment and the angiogenic response in this model of allergic inflammation of the airways. STEM

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Spatial and Phenotypic Characterization of Vascular Remodeling in a Mouse Model of Asthma

Cited by 15 publications

References 61 publications

Endothelial Cell–Specific Deletion of Transcription Factor FoxM1 Increases Urethane-Induced Lung Carcinogenesis

Endothelial Cell–Specific Deletion of Transcription Factor FoxM1 Increases Urethane-Induced Lung Carcinogenesis

IgE mediates broncho-vascular remodeling after neonatal sensitization in mice

CXCR2 Mediates the Recruitment of Endothelial Progenitor Cells During Allergic Airways Remodeling

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